Normal pregnancy represents a state of maternal tolerance to an antigenically disparate fetus. Some patients with recurrent spontaneous abortions are believed to lose the embryo through mechanisms involving immunologic rejection. Blocking factors have been described in the sera of normal pregnant women that may modulate the maternal immune response, preventing embryonic rejection during pregnancy. The mechanism by which they exert this effect is unknown. Pregnancy may induce unresponsiveness to the fetal allograft by the induction of antiidiotypic antibodies that, in turn, regulate the immune response at a cellular level. Such tolerance induction is similar to the situation encountered in renal transplantation, in which pre-transplant blood transfusions (BT) have a beneficial effect on graft survival. Preliminary data generated in our lab indicate that post-BT patients generate anti-HLA antiidiotypic antibodies which may be important in engendering allograft tolerance. We propose to investigate the sera of normal pregnant women and of patients with recurrent spontaneous abortion for evidence of anti-HLA antiidiotypic antibodies using enzyme immunoassay (EIA) techniques developed in our laboratory. We will isolate these factors by affinity chromotography techniques and study their effect on total IgG, IgM and specific anti-HLA IgG and IgM production by maternal control, and habitual abortion patient-derived isolated cultured lymphocytes in vitro. Using cultured lymphocytes we will study the in vitro effect of soluble HLA-Ag and HLA/anti-HLA immune complexes on total IgG, IgM and specific anti-HLA IgG, IgM production. It is anticipated that these experiments will provide data on mechanisms responsible for normal maternal-fetal tolerance and fetal rejection. The information obtained from these studies may be of help to design studies involving immunization to obtain active suppression of anti-HLA responses.